Specialist Viewpoint – or cholangiocarcinoma as they see it …

Article 2

Biomarkers for Cholangiocarcinoma

by Dr Abigail ZabronResearch FellowImperial College London

Thank you for this opportunity to contribute to the AMMF Viewpoint series. In this brief article I will explain some of the background to my work as a Research Fellow, part of which focuses on looking for new useful biomarkers for use in cholangiocarcinoma care.

What is a biomarker?

By definition, a biomarker is a “biological molecule found in blood, tissue or other body fluids (e.g. urine, bile) which reflects a normal or abnormal biological process”. In practice, these are the molecules underlying most medical tests on patient samples, including common blood and urine tests, and some biopsy analyses, and are vital in managing every disease, in diagnosis, assessing severity, and in monitoring response to treatment. Sometimes the biomarker is closely related to the disease process, e.g. raised blood sugars in diabetes. For a biomarker to be useful we don’t need to understand its role in the disease. What is important is its close match to the disease being present.

An ideal biomarker has various properties: It needs to be accurate and reliable between patients and different occasions, not to miss disease when it is present, but not to suggest disease in healthy patients or those with a different problem (the “sensitivity” and “specificity”). It needs to be found in a sample that is easy to obtain e.g. urine. Ideally the lab tests themselves should be simple and inexpensive to allow widespread use. And it should give as much information as possible, e.g. being higher where disease is more widespread than when it is just starting. It is a bonus if the biomarker gives clues as to the causes of a disease, thus highlighting potential avenues for new therapies.

In reality, biomarkers are rarely ideal. In cholangiocarcinoma this is a serious problem which prevents us from providing early and definite diagnosis and treatment.

Current biomarkers in cholangiocarcinoma

Although basic blood tests may raise suspicion of cholangiocarcinoma, there is no biomarker which can confirm the diagnosis with good accuracy. Medical teams rely on a combination of blood tests, imaging, and sometimes tissue samples (see Dr Khan’s Viewpoint article), and the diagnosis is still often unclear despite this. Blood tests for cancer biomarkers (“tumour markers”) are often sent, and may contribute to the diagnosis. Currently doctors often measure three such markers; Ca19-9, Ca125 and CEA. Ca19-9 can be raised in a range of benign conditions as well as pancreatic or stomach cancer and 10% people cannot produce Ca19-9 due to genetic variation, so their levels will never be raised. The test is falsely normal in up to half of patients with CC, failing to flag-up the diagnosis. Ca125 and CEA are also both often raised in a variety of other malignant and benign conditions. Ca125 is normal in up to half of patients with CC, and CEA only elevated in one-third of CC. Where samples of tissue are available, tests for biomarker proteins on the outside of the cell, CK7 and CK19, are useful but cannot confidently distinguish between CC and other cancers.

Because of this lack of accuracy, current biomarkers can only contribute to a diagnosis alongside other information. Available blood biomarkers have not changed in clinical practice over the last decade.

Future prospects

It is clear that better biomarkers are urgently needed in cholangiocarcinoma.

Recent research has seen us widen our net, analysing multiple different body fluids, and looking at a wide variety of different types of molecules, including DNA, small metabolites, as well as employing increasingly sophisticated analytical techniques and computer software to identify potential new markers. Work can use cell lines (populations of cells of different types which can be grown in the lab) or patient samples, the advantage of being “real” patient samples balanced against the convenience and control of a cell system. Whatever the system, the process normally involves making initial findings in a small group, then testing this in a larger group, before trialling this in a patient population comparing it against the current best options in clinical use.

Analysis of proteins in blood samples using a variety of chemistry techniques has identified several proteins (e.g. matrix metalloproteinase-7, interleukin-6) which may be raised in cholangiocarcinoma. However, these basic science results now need to be tested by looking for these proteins in a larger number of patients to ensure the initial results were correct.

Recently, advances have been made in studying bile fluid, which had previously been difficult to analyse. Bile is difficult to get, requiring endoscopy or drainage of the bile system to access it. However, the fluid comes directly from the bile ducts, close to where the cancer is developing, and therefore is thought might carry a high level of markers. This has found several promising candidates including MUC-1, NGAL and vimentin. Further work is progressing both in expanding these studies and in validating the identified proteins in larger numbers.

Urine has also proved an intriguing source of potential biomarkers, the advantage being the ease of obtaining a sample. Intriguing clues have been found looking not at the proteins but at the small waste products of metabolism, and future research will seek to identify such patterns which reflect the altered metabolic activity of a patient with CC.

Summary

Currently the diagnosis of cholangiocarcinoma is a difficult one, and the need for new biomarkers is urgent. There has been little advance in this area for several years. However, the last few years have seen advances in scientific techniques, and the expansion of this work and its application to larger test groups of patients will hopefully produce improved biomarkers for CC in the near future.